A Novel Thyrotropin Receptor Germline Mutation (Asp617Tyr) Causing Hereditary Hyperthyroidism

Nishihara, Eijun; Nagayama, Yuji; Amino, Nobuyuki; Hishinuma, Akira; Takano, Toru; Yoshida, Hiroshi; Kubota, Sumihisa; Fukata, Shuji; Kuma, Kanji; Miyauchi, Akira

doi:10.1507/endocrj.k07-088

Cited by 34 publications

(24 citation statements)

References 46 publications

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“…The variable expression of a heterozygous mutation has been reported in several other disorders such as hyperthyroidism due to the activating mutation of TSH receptor (52), myotonia congenita (53), retinitis pigmentosa (54), classical (55), and nonclassical congenital adrenal hyperplasia (56). The variability in phenotypic expression of heterozygous mutation may be conditioned by polygenic mechanism or by environmental factors (57,58).…”

Section: Discussionmentioning

confidence: 99%

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Tomar¹,

Bora²,

Singh³

et al. 2010

European Journal of Endocrinology

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Objective: Glial cells missing 2 (GCM2) gene encodes a parathyroid-specific transcription factor. We assessed GCM2 gene sequence in patients with isolated hypoparathyroidism (IH). Design: Case-control study. Methods: Complete DNA sequencing of the GCM2 gene including its exons, promoter, and 5 0 and 3 0UTRs was performed in 24/101 patients with IH. PCR-restriction fragment length polymorphism was used to detect a novel R110W mutation in all 101 IH patients and 655 healthy controls. Significance of the mutation was assessed by electrophoretic mobility shift assay (EMSA) and nuclear localization on transfection.Results: A heterozygous R110W mutation was present in DNA-binding domain in 11/101 patients (10.9%) and absent in 655 controls (P!10 K7 ). Four of 13 nonaffected first-degree relatives for five of these index cases had R110W mutation. Four heterozygous single nucleotide polymorphisms were found in the 5 0 region. One of the 11 patients with R110W also had T370M change in compound heterozygous form. Mutant R110W and T370M GCM2 proteins showed decreased binding with GCM recognition elements on EMSA indicating loss of function. Both wild-type and R110W mutant GCM2 proteins showed nuclear localization. Conclusions: The present study indicates a significant association of R110W variant with IH. Absence of effect of heterozygous R110W mutation on DNA binding and presence of the same mutation in asymptomatic family members indicate that additional genetic (akin to T370M change) or nongenetic factors might contribute to the expression of diseases in IH. Alternatively, it is possible that association of R110W with IH could be due to linkage disequilibrium with the unidentified relevant genes in IH.

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Section: Discussionmentioning

confidence: 99%

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Tomar¹,

Bora²,

Singh³

et al. 2010

European Journal of Endocrinology

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“…For amplification of Gαs exons 7-10, primers were: forward primer, 5'-ttc ttt ttc tcc caG ctt cct-3'; and reverse primer, 5'-GGt tGG tct GGt tGt cct cc-3'. Direct sequencing of PCR products was performed using the Bigdye terminator v1.1 cycle sequencing kit (Applied Biosystems, Foster city, ca) and an automatic ABI 3130 sequencer (Applied Biosystems), using each of the above primers or internal primers for exon 10 of the TSHR, as previously described [19,20]. results in a series of 45 aFtn, we found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsα gene (Table 1).…”

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confidence: 96%

Prevalence of TSH Receptor and Gs.ALPHA. Mutations in 45 Autonomously Functioning Thyroid Nodules in Japan

et al. 2009

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Abstract. Somatic mutations of the thyrotropin receptor (TSHR) gene and the gene encoding the α subunit of the stimulatory GTP-binding protein (Gsα) are the main cause for autonomously functioning thyroid nodules (AFTN) in iodine-deficient regions of the world. In iodine-sufficient regions, including Japan, the genetic relevance of AFTN is unclear. In a series of 45 Japanese subjects with AFTN, exons 9 and 10 of the TSHR and exons 7-10 of Gsα, where the activating mutations have been found, were analyzed using direct sequencing. We found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsα gene. The most frequent mutation in TSHR was Met453Thr (10 cases), followed by clustered residues from codons 630 through 633 on TSHR (7 cases). Mutations of Gsα were detected at codon 201 in 5 cases and at codon 227 in 2 cases. No patients had coexistent TSHR and Gsα mutations in the same nodule. All mutated residues but one, which was deleted at codon 403 on the TSHR gene, are constitutively active. The prevalences of a germline polymorphism of Asp727Glu on the TSHR gene and incidental papillary thyroid carcinoma in thyroid surgical specimens were similar to those reported in other studies. In the present study, more than half of the cases with AFTN had a somatic activating mutation either of the TSHR or Gsα gene, despite their high iodine intake.

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“…A delayed and progressive onset of hyperthyroidism with mild clinical manifestations has previously been observed (1,2,11,14,17). However, to our knowledge, there are no prior reports on familial nonautoimmune hyperthyroidism with all affected individuals presenting in adulthood with subclinical hyperthyroidism.…”

Section: Discussionmentioning

confidence: 77%

“…Serum TSH-binding inhibitory immunoglobulins, anti-Tg antibodies, anti-TPO antibodies, and Tg were measured with an electrochemiluminescent immunoassay (ECLusys TRAb, ECLusys Anti-Tg, ECLusys Anti-TPO, and ECLusys Tg; Roche Diagnostic, Mannheim, Germany). Total thyroid volume and the size and pattern of thyroid nodule were measured using ultrasound diagnostic equipment, as reported previously (17).…”

Section: Thyroid Function Analysis and Thyroid Volumementioning

confidence: 99%

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Subclinical Nonautoimmune Hyperthyroidism in a Family Segregates with a Thyrotropin Receptor Mutation with Weakly Increased Constitutive Activity

Nishihara

Chen

Higashiyama

et al. 2010

Thyroid

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Background: Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene. Methods: The proband was a 64-year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism. Results: A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway. Conclusion: Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial.

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A Novel Thyrotropin Receptor Germline Mutation (Asp617Tyr) Causing Hereditary Hyperthyroidism

Cited by 34 publications

References 46 publications

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Prevalence of TSH Receptor and Gs.ALPHA. Mutations in 45 Autonomously Functioning Thyroid Nodules in Japan

Subclinical Nonautoimmune Hyperthyroidism in a Family Segregates with a Thyrotropin Receptor Mutation with Weakly Increased Constitutive Activity

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